by Dr. Mario Koksch, Vice President and General Manager, Flow Cytometry Business Unit at Beckman Coulter Life Sciences
The marathon for IVDR compliance has added a few more laps beyond the May deadline, but the earlier labs prepare the better. While the In-Vitro Diagnostics Regulation (IVDR) will raise the standards of in vitro diagnostics, it is also expected to complicate compliance not only for manufacturers but also for laboratories. In fact, many laboratories have not achieved IVDR compliance over the past five years to meet plans established in 2017.1 While many were involved in the battle against COVID-19, others were not aware of the repercussions of the new Laboratory Developed Test (LDT) regulations.
The initial May 2022 deadline has been extended, but that does not relieve manufacturers and laboratories of the responsibility to undertake critical tasks ahead. On the contrary, affected organizations must see this as an opportunity to take immediate action to add to their competitiveness and credibility when the regulations will be in full effect. Thus, they will reestablish their top spots in the new era of high-quality IVD supply in Europe.
Why was the IVDR necessary?
First developed in 1998, the In Vitro Diagnostic Directive (IVDD) was dated and did not impose thorough inspection of medical devices, laboratory tests and assay kits. If an IVD bypassing evaluation was faulty, it could have easily caused misdiagnosis and eventually an erroneous treatment decision, which could have had life-threatening consequences.
The European Union proposed IVDR 2017/746 to bridge the safety gaps in IVDs and LDTs.
How is IVDR different from IVDD?
We can categorize the modifications of IVDR as follows:
- Compulsory certification by third parties - notified bodies - according to the risk level of the IVD devices
- Additional requirements for proving scientific validity and clinical relevance
- New requirements for post-market performance follow-up
- Increased control over LDTs
How will these changes affect IVD manufacturers?
The most noteworthy change is the involvement of notified bodies. With the implementation of IVDR, the percentage of IVDs requiring notified body approval is expected to increase from 15% to 85%. In addition, the EU significantly expanded the evaluation criteria for notified bodies. Besides analytical performance, an IVD will now be investigated for its clinical performance, the accuracy of technical documentation, supply management, and performance in the market.
To meet the demands of such stringent requirements, manufacturers need to invest substantial time and financial resources. Failure to do so means manufacturers cannot launch their products in Europe.
Demonstrating the analytical and clinical performances of IVDs is an intricate process, so manufacturers will have to upgrade their quality management system. More importantly, they may need to hire new staff for regulatory compliance roles to handle their upgraded quality management systems. So, the road leading to the initial certification alone demands a sacrifice of time and budget, which does not even include fees payable to the notified bodies.
To complicate matters, there is a reduction in the number of notified bodies qualifying for IVD certification under IVDR definitions.1 These few notified bodies will have to handle a massive number of applications. That’s why, regardless of the intimidating data and documentation process, manufacturers must start preparing the necessary documents as soon as possible to avoid a possible backlog in the future.
Unlike IVDD, IVDR strongly emphasizes IVD performance after the initial product launch, demanding a so-called cradle to grave performance evaluation. Manufacturers must prepare a post-market performance follow-up plan to abide by this additional requirement. Subsequently, they need to stick to it by performing regular risk management and performance evaluation.
Looking at all the implications above, it is not difficult to grasp the necessity of a timely start to the compliance marathon. Delays in any of the steps can subsequently delay the approval, licensing, and launch of an IVD, potentially causing financial loss to the company for both new and legacy products; these delays must be remediated in time for products to continue being commercialized. On the other hand, achieving early compliance will help manufacturers stand out when there is a scarcity of fully compliant manufacturers in Europe. That’s why, despite extended deadlines, manufacturers should strive to obtain CE marks for their IVDs as early as possible.
Will clinical laboratories be affected by the IVDR?
Yes, in vitro diagnostic assays designed and manufactured in health institutions are within the scope of the IVDR. This is a major change for laboratories relying on user-defined tests and home-brew assays, as these were not regulated under the previous directive (IVDD). Additional requirements must be met by laboratories that continue to rely on user-defined tests after IVDR is in full force.
IVDR will perhaps have a bigger impact on clinical laboratories than on manufacturers. Simply put, a laboratory wanting to produce LDTs will be liable for several IVDR rules before starting production.
What happens if there is no CE-marked equivalent to study a rare disease?
The great news is that laboratories can continue to make their own LDT in that case, provided they meet certain criteria outlined in Article 5.5 of IVDR 2017/746, including:
- The laboratory must be a European health institution.
- It must still comply with the General Safety and Performance Requirements (GSPR), as indicated in Annex I.
- It must have a Quality Management System compliant with the Medical Laboratories – Requirements for Quality and Competence section of ISO-15189, or applicable national provisions including accreditation.
- Most importantly, the laboratory must justify why they need to use their own LDTs by demonstrating that there is no substitute test in the market for their research purposes.
What are the unique difficulties of the three most-likely scenarios?
Under IVDR, laboratories can simply buy a CE-marked IVD, they can make their own LDT despite the existence of a commercially available IVD, or they can produce their own LDT because no alternative exists in the market.
All three scenarios will see clinical laboratories performing extra tasks.
If the lab can find CE-IVD reagents with the adequate intended use, they may have to run additional assay-performance validations to comply with applicable standards and regulations.
For laboratories wishing to continue producing LDTs, they need to determine if there is a CE-marked IVD alternative. It can be a challenging process: to manufacture LDTs despite equivalent IVD alternatives, a laboratory will have to take on the role of a manufacturer. Most clinical laboratories don’t have the resources to complete that process – they’re meant to produce diagnostic results, not assays.
Still, certain laboratories must continue to produce their own LDTs, primarily when it comes to rare diseases. This would require upgrading equipment, protocols, and quality management systems. This creates a challenging scenario, and one that requires managers to research and evaluate whether it’s feasible for them to invest in LDTs going forward, and what might be able to be replaced with CE-marked alternatives or how IVD manufactures can help.
Flow cytometry laboratories face a particularly unique circumstance. Because flow cytometry assays rely on unique combinations of antibodies, it may be difficult to find their CE-marked alternatives. The lab can resume their LDT production, but they must still upgrade their quality management systems, laboratory equipment, and protocols.
All three scenarios come with a unique set of challenges, which could be daunting, especially for small-scale laboratories studying rare diseases. If they do not have the necessary budget and a clear action plan, they cannot showcase their tests in Europe.
How should laboratories approach IVDR Compliance?
Laboratories should take the following actions:
- Determine which of their tests are CE-marked IVDs, modified IVDs, or LDTs.
- Determine which LDTs or modified IVDs can be replaced by an IVDR-compliant CE-marked IVD.
- Enquire with CE-marked IVD suppliers within their budget.
- For LDTs, justify why they need to continue the production by proving the lack or absence of a CE-marked alternative.
- Enquire whether they can be defined as a European health institution that meets all requirements of IVDR Article 5.5 to carry out LDT production, or if they need to comply with full IVDR.
What is the role of IVD manufacturers in the IVDR compliance marathon?
Reaching out to laboratories Beckman Coulter Life Sciences works with, we learned many of them were concerned about the upcoming changes and needed external resources. As manufacturers, we need to dedicate ourselves to becoming the pioneers of IVDR compliance to support laboratories in their IVDR journey.
Over the past four years, Beckman Coulter Life Sciences has been striving to expand its CE-IVD portfolio by making our products IVDR-compliant. We took particular interest in clinical flow cytometry IVDs by providing resources and assistance for laboratories in this field.
As of January 2022, we have received an EU Quality Management System Certificate under the IVDR for over 200 flow cytometry reagents at our manufacturing facility in Marseilles, France. Our ongoing goal is to raise this number to more than 300, and we continue to dedicate resources to achieving this goal.
Besides obtaining certificates for devices, we have also been actively working with laboratories to educate them about the intricacies of IVDR compliance. One of our most recent tools is the Digital Campus, an interactive customer resource platform that informs customers about our IVDR-compliant instruments and workflows. The platform will also host educational sessions to help prepare laboratories for the fast-approaching IVDR deadlines. Comprehensive collaboration efforts will help customers reach the IVDR finish line on time.
Is it worth pursuing IVDR compliance?
There is no doubt that IVDR compliance will be a challenging mission for everyone involved. Tighter regulations over IVDs and LDTs will extend the manufacturing period and increase the associated costs.
That said, we believe that the IVDR will raise healthcare standards in Europe by improving quality assessment and risk management for IVDs. This will positively impact healthcare professionals by helping them to make treatment decisions with certified and more accurate tests. Those who become part of the new system will strengthen their positions in the European in vitro diagnostic market.
Overall, the results of IVDR compliance will be rewarding despite the challenges, so we strongly urge manufacturers and laboratories to take it seriously.
References
1. https://www.biomedeurope.org/images/news/2021/BioMed_Alliance_IVDR_statement_final.pdf
About the Author: Mario Koksch, Vice President of the Flow Cytometry business unit, joined Beckman Coulter Life Sciences in 2000. He is responsible for the flow cytometry business and has day-to-day responsibility for strategic marketing, business growth, and development of the company's diversified clinical and research portfolio of flow cytometry hardware, software, reagents and assays. He also oversees the company’s manufacturing centers in Marseille, Bangalore and Suzhou. Koksch has more than 20 years of experience working in the flow cytometry field and has a Ph.D. and medical degree from Leipzig University (Germany), and a Marketing M.B.A. from the University of Applied Science Koblenz-Remagen (Germany).